Immunologically mediated skin diseases

Immunologically Mediated Skin Diseases
Wat Mitthamsiri, M.D.
Allergy and Clinical Immunology Unit
Department of Medicine
King Chulalongkorn Memorial Hospital

Outline
 Epidermal and epidermal-dermal cohesion
 Differential Dx of vesicles/bullae
 Pemphigus vulgaris
 Pemphigus foliaceus
 Bullous pemphigoid
 Gestational pemphigoid
 Cicatricial pemphigoid
 Dermatitis herpetiformis
 Linear IgA bullous dermatosis
 Epidermolysis bullosa acquisita
 Paraneoplastic pemphigus

Epidermal and epidermal-dermal
cohesion
 Desmosome
 Hemidesmosome
 Epidermal basement membrane

S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.

cohesion
 Desmosome’s main components
 Plakins
 Armadillo proteins
 Desmosomal cadherins


cohesion
 Hemidesmosome’s main components
 Plakins homologues
 Integrins
 Collageneous transmembrane protein


cohesion
 Epidermal basement membrane
 Collagen type IV
 Laminins
 Nidogens
 Perlecan


cohesion
 Proteins in desmosomes, hemidesmosomes

and epidermal basement membranes are
targeted by autoimmune in skin blistering
diseases


 PF; Pemphigus foliaceus, PNP; Paraneoplasic pemphigus, PV; Pemphigus

vulgaris, SPD; Subcorneal pustular dermatosis


 BP; Bullous pemphigoid, CP; Cicatricial pemphigoid, LAD; Linear IgA

dermatosis, PG; Pemphigoid gestationis, EBA; Epidermolysis bullosa aquisita


Differential Dx of vesicles/bullae

Primary mucocutaneous diseases
 Primary blistering diseases (autoimmune)
 Pemphigus vulgaris
 Pemphigus foliaceus
 Bullous pemphigoid
 Gestational pemphigoid
 Cicatricial pemphigoid
 Dermatitis herpetiformis
 Linear IgA bullous dermatosis
 Epidermolysis bullosa acquisita

DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.

Primary mucocutaneous diseases
 Secondary blistering diseases
 Contact dermatitis
 Erythema multiforme
 Stevens-Johnson syndrome
 Toxic epidermal necrolysis
 Infections
 Varicella/zoster virus
 Herpes simplex virus
 Enteroviruses, e.g., hand-foot-and-mouth disease
 Staphylococcal scalded-skin syndrome
 Bullous impetigo

Systemic diseases
 Autoimmune
 Paraneoplastic pemphigus
 Infections
 Cutaneous emboli
 Metabolic
 Diabetic bullae
 Porphyria cutanea tarda
 Porphyria variegata
 Pseudoporphyria
 Bullous dermatosis of hemodialysis
 Ischemia
 Coma bullae


Pemphigus classification
Type
Pemphigus vulgaris
Pemphigus foliaceus

Paraneoplastic pemphigus
IgA pemphigus

Form
Pemphigus vegetans; Localized
Drug-induced
Pemphigus erythematosus; Localized
Fugo selvagem; Endemic
Drug-induced
Subcorneal pustular dermatosis
Intraepidermal neutrophilic IgA dermatosis


Pemphigus vulgaris
 Epidemiology
 Men = Women, except for some countries
 Mean age 40-60 years, but range is broad
 Incidence can be 7.6-100/1 million

population/year (depends on ethnic group)


Pemphigus vulgaris
 Etiology
 Genetic predisposition: HLA-DRB1*0402, -

DQB1*0503.
 Ab against desmoglein 3 (Dsg3) and later
desmoglein 1 (Dsg1)

 The bound Ab activate proteases that damage the

desmosome  Acantholysis
 Drugs, esp. without sulfhydryl groups
 Beta-blockers, cephalosporins, penicillin, and

rifampicin

Sterry, et al., Dermatology , 2006.

Pemphigus vulgaris
 Clinical presentation
 Typically begins on mucosal surfaces (mostly oral)

and progresses to involve the skin
 Fragile, flaccid blisters that rupture to produce
extensive denudation of mucous membranes and
skin
 Involved areas: mouth, scalp, face, neck, trunk,
genitalia, mechanically stressed areas, nail fold,
intertriginous areas (eg. axilla, groin)
 May be associated with severe pain and pruritus

Sterry, et al., Dermatology , 2006


Pemphigus vulgaris
A: PV with marked erosions,

B: PV with oral ulceration


Pemphigus vulgaris


Pemphigus vulgaris
 Nikolsky sign:
 True Nikolsky sign: Gentle rubbing allows one to
separate upper layer of epidermis from lower, producing
blister or erosion
 Fairly specific for pemphigus
 Pseudo-Nikolsky sign (Asboe–Hansen sign):
 Pressure at edge of blister makes it spread
 Less specific, seen with many blisters eg. TENS, SJS

Pemphigus vulgaris
 Histopathology


Pemphigus vulgaris
 Immunopathology
 Direct immunofluorescence of perilesional skin
 Deposition of IgG (100%), C3 (80%) or IgA (20%), as
well C1q in early lesions
 Hallmark: Abs surround the surface of individual
keratinocytes
 Indirect immunofluorescence: Using monkey

esophagus

 90% of sera show positive reaction; titer can be used to

monitor disease course.


P. vulgaris vs P. foliaceus


Pemphigus vulgaris
 Immunopathology
 ELISA:
 More sensitive and specific than immunofluorescence for
DDx PV from PF
 Can be used to identify:
 Anti-Dsg3 only: patient with predominantly mucosal
disease
 Anti-Dsg1and anti-Dsg3: patient with widespread
disease


Pemphigus vulgaris
 Treatment
 Systemic corticosteroids
 Main cause of morbidity and mortality is

corticosteroid side-effects  always combined with
steroid-sparing agents
 Screen for osteoporosis and latent tuberculosis
 Treatment of choice.
 Pulse of prednisolone 1 g/day q 3-4 wk

 Plus single dose of cyclophosphamide 7.5–15

mg/kg divided into 1–2 mg/kg/day


Pemphigus vulgaris
 Treatment
 Prednisolone-azathioprine therapy:
 prednisolone 1.5–2.0mg/kg and azathioprine

2.5mg/kg
 If blister formation is not suppressed within 1 week,
double the prednisolone dose
 Once blister formation is suppressed, taper to
maintenance dose of prednisolone 8mg daily and
azathioprine 1.5mg/kg daily

Pemphigus vulgaris
 Treatment
 Alternative immunosuppressive agents:
 Chlorambucil 0.1–0.2mg/kg daily
 Cyclosporine 5.0–7.5mg/kg daily
 Mycophenolate mofetil 2.0g daily
 Topical measures
 Local anesthetic gels in the mouth before meals
 Antiseptics and anticandidal measures may also be useful
 Therapy-resistant course
 Drastic measures include high-dose IVIG or column immune
absorption of autoantibodies
 Immunosuppressive therapy must be continued or a rebound
invariably occurs

Pemphigus foliaceus
 Epidemiology
 Prevalence is less than PV
 Dependent of geographic location
 All age groups affected


Pemphigus foliaceus
 Etiology
 Autoantibodies against Dsg1
 Rarely Ab shift  later are formed against Dsg3 and
patient develops PV
 More often drug-induced than PV
 Drugs with sulfhydryl groups
 Mechanism might be interference to adhesion
molecules, modification of antigenicity and regulation of
immune response
 May be caused by sunburn or as paraneoplastic sign

Pemphigus foliaceus
 Sites of predilection: scalp, face, chest, and back

(seborrheic areas) with diffuse scale and erosions
 Primary lesion: Small flaccid blister (difficult to find)
 Can progress to involve large areas (exfoliative
erythroderma)
 Facial rash sometimes butterfly pattern
 Oral mucosa usually spared
 Individual lesions are slowly developing slack blisters
that rupture easily, forming erosions and red-brown
crusts
 Several clinical variants

Pemphigus foliaceus
 PF with diffuse superficial erosion


Pemphigus foliaceus


Pemphigus foliaceus
 Exfoliative erythroderma


Pemphigus foliaceus
 Histopathology
 Blister forms in stratum corneum or stratum

granulosum
 Acantholysis rarely seen
 Usually just a denuded epithelium and sparse
dermal perivascular inflammation


Pemphigus foliaceus
 Histopathology


Pemphigus foliaceus
 Immunopathology
 Direct and indirect immunofluorescence:
 Superficial deposition of IgG
 ELISA
 IgG antibodies against Dgs1


Pemphigus foliaceus
 Treatment
 Same approach as PV
 Usually more responsive to therapy
 Dapsone may be helpful


Bullous pemphigoid
 Epidemiology
 Most common autoimmune bullous disease
 Incidence range 14-472/1,000,000 yearly
 Favors elderly (one estimate 300x more likely at

90 years of age than at 60 years of age)
 No known ethnic, racial or sexual predilection
 6-40% mortality in 1 year


Bullous pemphigoid
 Etiology

 AutoAb directed against two hemidesmosomal

proteins:

 BP 230 or BP antigen 1 (BPAG1)
 BP 180 or BP antigen 2 (BPAG2)

 The binding of autoAb leads to complement

activation, attraction of eosinophils, release of
proteases, and separation between the epidermis
and dermis
 Less common causes: drugs (benzodiazepine,
furosemide, penicillin, sulfasalazine), sunlight, and
ionizing radiation.


Bullous pemphigoid
 Before blisters develop, pruritus, dermatitic, and

urticarial lesions may be present. The blisters tend
to develop in these areas.
 Tense blisters, often have a fluid level, and can
reach 10cm in diameter
 Most common on lower abdomen, thighs and
flexor forearms, but can occur anywhere
 Oral mucosal involvement in 20%
 Several clinical variants



Bullous pemphigoid


Bullous pemphigoid
 Urticarial lesions


Bullous pemphigoid
 Histopathology
 In the prebullous lesions, the presence of

unexpected eosinophils is a good clue
 Later subepidermal blister formation
 Two forms:

 Cell-rich form: contains many eosinophils and

neutrophils
 Cell-poor form: sparse infiltrate

 Lamina lucida = roof of the blister
 Lamina densa = floor of the blister

Bullous pemphigoid


Bullous pemphigoid
 Immunopathology and other lab tests
 Direct immunofluorescence:
 Band of IgG and C3 along basement membrane zone.
 Indirect immunofluorescence:
 AutoAb usually attach to just the roof of the blister
(bottom of the basal cell), but can appear on the dermal
side or in both locations.
 7-80% of patient have IgG against normal stratified
squamous cell epithelium

Bullous pemphigoid
 Direct immunofluorescence


Bullous pemphigoid
 Indirect immunofluorescence


Bullous pemphigoid
 Immunopathology and other lab tests
 ELISA
 Identifies Ab against both BPAG1 (230kd) and BPAG2
(180kd) in 60–80% of patients
 Those directed specifically against the NC16 epitope of
BP 180 correlate best with disease course
 Elevated ESR
 Eosinophilia
 Increased IgE

Bullous pemphigoid
 Treatment
 Mainstay is systemic corticosteroids:
 Prednisolone 0.75-1 mg/kg daily
 As soon as control is reached, tapering to maintenance dose

of 8 mg daily.
 Try to taper to alternate-day dosage for adrenal-sparing effect
 Most widely used steroid-sparing agent:
 Azathioprine, cyclophosphamide
 Mycophenolate mofetil also appears promising.
 MTX 15–20 mg weekly is also effective; it can be combined
with high potency topical corticosteroids during the 4-6
weeks of induction

Bullous pemphigoid
 Treatment
 Some patients do well on high-potency topical
corticosteroids with less systemic steroid side effects
 Large open blisters and erosions may require topical
antiseptics
 Some patients with localized disease had advantage
from topical tacrolimus


Gestational pemphigoid
 Epidemiology
 Occurs in 1:10,000–50,000 pregnancies (least

common dermatitis specific to pregnancy)
 If same father, high likelihood of recurrence in
subsequent pregnancies
 No maternal risk
 No increase in birth defects
 Complications of pregnancy in 15–30%
 8% fetal death rate.


 Etiology
 Mothers often HLA-B8, -DR3, or -DR4
 Father often HLA-DR2.
 Possible that mothers are sensitized against

placental antigens
 IgG1 autoAb against

 BP 180 (NC16 domain)
 BP 230 (less often)


 Sites of predilection :
 Protuberant abdomen and extremities
 Mucosal involvement 20%.
 Grouped stable blisters with pruritus develop in

2nd/3rd trimester and persist until delivery
 Rarely appear postpartum
 Resolve within 3months
 Occasionally recur with menses or ingestion of OCP
 Tends to be worse in next pregnancy.
 AutoAb cross the placenta
 Newborn can have blisters for a few weeks.


 Histopathology
 Subepidermal blister, usually with cell-rich pattern


 Immunopathology and other labs
 Band of C3 along BMZ; occasionally IgG; all the others
uncommon.
 IgG Ab cannot always be demonstrated directly, but their
strong complement-fixing properties allow
identification (herpes gestationis factor).
 IgG attaches to the blister roof
 Often hypereosinophilia.

 Treatment
 Topical corticosteroids: Usually ineffective
 Prednisolone 0.5 mg/kg/d, then try taper to

lowest maintenance dose
 Severe cases:

 High-dose IVIG, immune absorption, or cyclosporine

 Persistence after delivery
 Luteinizing hormone-releasing hormone might be
considered

Cicatricial pemphigoid
 Epidemiology
 Incidence about 1/1,000,000 population/year
 Female:Male about 1.5-2:1
 Mean age of onset about early to middle 60s
 No ethnic/racial factor mentioned


 Etiology
 Genetics: HLA DQB1*0301
 Disease susceptibility marker: Amino acid position

57 and 71-77 of DQB1 protein
 Several different target antigens
 BP 180 (BPAG2)
 BP 230 (BPAG1)
 α6β4 integrin
 Laminin5

 Topical ophthalmologic medications



 Conjunctiva:
 Affected in 75% of cases
 Starts unilaterally, usually bilateral within 2years
 Adhesions, ectropion, corneal damage found
 Oral mucosa:
 Affected in 75% of cases
 Vesicles, blisters, erosions, scarring
 Desquamative gingivitis commonly occurs
 Much less painful than PV.

 Esophagus and larynx: Strictures
 Genitalia:
 In women: narrowing of vaginal orifice
 In men: adhesions between glans and foreskin
 Rectal mucosa
 Skin: (25% of cases)
 Usually generalized disease similar to BP
 Localized form (Brunsting–Perry disease)
 Recurrent blisters develop on persistent plaques



 Histopathology
 Subepidermal blister
 Lymphocyte and histiocyte infiltration
 Variable neutrophil and eosinophil infiltration
 In elderly, maybe “cell poor”
 Older lesion
 Fibrobrast proliferation
 Lamellar fibrosis


 Immunopathology
 IgG (60%) and C3 (40%) along BMZ in lesional skin
 Occasionally IgM and IgA
 In normal skin, about 30% IgG
 IgG reactivity can be seen on either side of the split, or
in both locations, depending on target antigen
 Patient with both IgG and IgA often has worse

prognosis


 Immunopathology
 Identify target antigens:
 BP 180 is most common; Mucosal and skin disease
 α3 subunit of laminin 5 (formerly known as epiligrin);
Mucosal and skin disease
 α6β4-integrin: only ocular disease.


 Treatment


Dermatitis herpetiformis
 Epidemiology
 About 10-39/100,000 population/yr in caucasion
 Men are affected twice as often women
 Disease of young adults
 Starts at any age
 Age of about30s to 40s are the most common


 Etiology
 Abnormal immune response to gluten
 Most important sensitizing protein is gliadin
 AutoAb against tissue transglutaminase also cross-

react with the similar epidermal transglutaminase
 Strong HLA association
 90% of patients: HLA-DQ2 (A1*0501 and B1*02)
 Other 10%: HLA-DQ8 (A1*03, B1*03)
 Other genetic factors are involved


 Sites of predilection:
 Knees and elbows (Cottini type)
 Buttocks and upper trunk
 Facial involvement rare.
 Hallmark: intensely pruritic or burning tiny

vesicles (usually scratched away)
 Undisturbed lesions: rim of peripheral vesicles
arranged in herpetiform fashion
 Larger blister (Less often)

 Occasional enteropathy
 Malabsorption
 Voluminous loose stools
 Weight loss
 Occasional association with other autoimmune

diseases:

 Diabetes mellitus
 Pernicious anemia
 Thyroid disease
 Vitiligo.


 Iodine intolerance and flare with iodine exposures
 Iodine challenge or iodine patch test are old diagnostic
measures.
 Spontaneous remissions may occur, but disease

often lifelong
 Increased risk for MALT B-cell lymphoma


 Pattern of distribution


 Histopathology
 Hallmark: Neutrophilic microabscesses in the

papillary dermis
 Often admixed with eosinophils
 Edema leads to subepidermal blister formation


 Histopathology


 Granular deposits of IgA in dermal papillae
 Sometimes granular-linear along BMZ present in 95% of
patients and persist long after therapy is started
 IgA Ab against smooth muscle endomysium present in
80%.


 ELISA
 IgA-Ab against tissue transglutaminase in at least 80%
 Antigliadin Ab (less specific)
 Jejunal biopsy:
 Flattening of villi (85%) with intraepithelial
lymphocytes in 100%


 Treatment
 Mainstay = gluten-free diet

 Dapsone: Usually 25–50 mg is sufficiently effective

Linear IgA bullous dermatosis
 Epidemiology
 Presenting age about 40s
 Uncommon disease
 Female: male ratio 2:1.


 Etiology
 Genetic: HLA-B8?, TNF2 allele
 AutoAb (mainly IgA1) against:
 Lamina lucida
 Type VII collagen in lamina densa
 Several drugs
 Vancomycin (most common)
 Penicillin
 Sulfamethoxazole/trimethoprim
 Atorvastatin

 May be identical to dermatitis herpetiformis (eg.

severe pruritus) but without gastrointestinal
involvement
 Can be resemble BP or even cicatricial pemphigoid
with ocular involvement
 Up to 70% have mucosal involvement
 Papulovesicles, bullae, and/or urticarial plaques
predominantly on central or flexural sites

 Histopathology


 Immunopathology
 IgA-Ab at dermal-epidermal basement membrane zone
 Additional tests:
 Eye examination
 Jejunal biopsy (to exclude celiac disease)


 Direct immunofluorescence


 Treatment
 Corticosteroids: Best for lamina lucida type
 Dapsone: Helpful for lamina densa type
 Gluten-free diet? Mostly can not help


Epidermolysis bullosa acquisita

 Epidemiology
 Uncommon disorder
 Seen in adults in 4th–5th decades
 No gender, geographic, ethnic predisposition


 Etiology
 Exact mechanism is unknown
 AutoAb (IgG) directed against type VII collagen (a

component of the lamina densa)
 HLA DR2 might play some role



 Acral mechanobullous form
 Fragile skin and blisters on backs of hands healing with
milia and scarring
 Nail dystrophy
 Foot involvement is clue to EBA
 Inflammatory form
 Similar to BP with stable blisters
 Less often resembles cicatricial pemphigoid or
dermatitis herpetiformis
 Heals with scarring
 About 50% of patients have mucosal involvement.


 Associated diseases:
 Inflammatory bowel disease
 Lupus erythematosus
 Rheumatoid arthritis


 Histopathology
 Subepidermal blisters
 Clean separation between epidermis and dermis
 Variable cellular infiltration
 Degree of infalmmatory cell infiltration reflects

degree of clinical inflammation


 Immunopathology
 Deposition of IgG (rarely IgA) in BMZ.
 IgG with ability to bind complement found in 50%.
 IgG binds to base of blister
 ELISA
 Antibodies against type VII collagen.


 Direct immunofluorescense


 Epidemiology
 Rare but real incidence is unknown
 A report found just 12 from 100,000 NHL patient
 Suspected of misdiagnosed as erythema

multiforme, TENS, SJS and drug rash


 Etiology
 Most often associated with NHL, leukemia (CLL),

Castleman tumor, or thymoma
 Not associated with SCC or adenocarcinoma
 Anti-Dsg Ab: pathogenetically most important
 Presumably cross-reactions between tumor Ag and
desmosomal Ag (eg. plakins, desmogleins, and
bullous pemphigoid Ag) Additional from PV/PF
 HMI also plays a role but not CMI

 Tumor associated with paraneoplasic pemphigus


 The most constant feature is severe, persistent

painful stomatitis extending from the lips into the
pharynx, larynx, and esophagus
 Conjunctival involvement may lead to blindness
 Cutaneous changes are polymorphic, ranging from
erythematous macules to lichenoid papules to
blisters and erosions

 Histopathology: Variable
 Acantholysis
 Lichenoid
 Interface change
 Non-specific change of inflammation and

ulceration


 Immunopathology
 If indirect immunofluorescence is positive on rat

bladder epithelium (Ab also binds to columnar and
transitional epithelium), this strongly suggests
paraneoplastic pemphigus
 The combination of IgG antibodies against plakins
and desmogleins confirms the diagnosis
 Also granular/linear complement deposition along
epidermal basement membrane zone

 Management


 Treatment
 Treating the underlying tumor comes first
 The prognosis correlates with the response
 There is no consensus on what immunosuppressive

regimen to employ, especially in patients required
chemotherapy
 Recent reports of good success with anti-CD20
antibodies (rituximab)


Immunologically mediated skin diseases

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